Wild Biotech co-founder Neta Raab

Two Church lab vets, a se­cre­tive in­sti­tute and an Is­raeli bil­lion­aire hunt for drugs in the guts of wild an­i­mals

Over the last four years, Ne­ta Raab and Ido Bachelet have re­ceived hun­dreds of padded card­board box­es con­tain­ing frozen poop from wild an­i­mals on five dif­fer­ent con­ti­nents.

The pack­ages came reg­u­lar­ly to their lab out­side Tel Aviv, sent from a squad of zo­ol­o­gists and spe­cial­ized Is­raeli army vet­er­ans who tracked enough an­i­mals to fill a Rud­yard Kipling nov­el, rush­ing to col­lect vul­ture and rhi­no and frog sam­ples with­in an hour of ex­tru­sion. Raab and Bachelet care­ful­ly opened the box­es, re­mov­ing the sam­ples from plas­tic-wrapped tubes and then us­ing spe­cial­ized mag­net­ic beads to fish out the bac­te­r­i­al DNA in­side for se­quenc­ing.

The re­sult of that ef­fort ap­peared Thurs­day in Sci­ence, where Raab, Bachelet and promi­nent Is­raeli com­pu­ta­tion­al bi­ol­o­gist Er­an Se­gal pub­lished what amounts to the largest data­base ever as­sem­bled of the mi­cro­bio­me, or gut bac­te­ria, in­side dif­fer­ent mem­bers of the an­i­mal king­dom. Sam­pling near­ly 200 an­i­mals, they doc­u­ment­ed 5,000 genomes across over 1,200 dif­fer­ent bac­te­r­i­al species, most of which had nev­er been seen be­fore.

Jack Gilbert

It’s a ma­jor sci­en­tif­ic achieve­ment, out­side ex­perts say, one that will al­low the grow­ing num­ber of re­searchers study­ing the mi­cro­bio­me in­side par­tic­u­lar an­i­mals, in­clud­ing hu­mans, to fit their find­ings in­to a broad­er con­text. But for Raab and Bachelet, two vet­er­ans of the George Church Lab, it’s al­so a vast trove of ge­net­ic in­for­ma­tion that could be mined for new drugs on a long list of dis­eases.

They’ve launched a com­pa­ny, Wild Biotech, to be­gin turn­ing the genes they found in­to ther­a­pies for im­muno­log­i­cal, in­flam­ma­to­ry and gas­troin­testi­nal con­di­tions. The idea is that these bac­te­ria have, over mil­lions of years, evolved pro­teins to car­ry out a wide range of unique func­tions for their hosts. Tap­ping and en­gi­neer­ing those pro­teins could help cor­rect prob­lems in hu­mans.

“This re­source re­al­ly does cre­ate a plat­form — a spring­board if you will — to ac­cel­er­ate re­search, to help us lever­age the mi­cro­bio­me in treat­ing dis­ease, im­prov­ing health, restor­ing ecosys­tems,” says Jack Gilbert, a mi­cro­bial ecol­o­gist at UC San Diego who is not in­volved in the re­search or the com­pa­ny.

Time­wise, he adds, bac­te­ria have a leg up on any med­i­c­i­nal chemist in a drug lab. “If you think about it, na­ture has been ex­per­i­ment­ing with vari­ants in mi­cro­bial chem­istry for bil­lions of years,” he says. “That’s a lot of ex­per­i­men­ta­tion — way more than any hu­man en­deav­or could hope to achieve.”

Dan Littman

Wild Biotech joins the long list of com­pa­nies that have raised bil­lions to lever­age sci­en­tists’ grow­ing un­der­stand­ing of the hu­man mi­cro­bio­me in­to new drugs for can­cer or in­fec­tious dis­ease. Those ef­forts, though, have large­ly fo­cused on giv­ing peo­ple tablets con­tain­ing strains of liv­ing bac­te­ria from hu­mans, re­ly­ing on the con­flu­ence of hun­dreds of dif­fer­ent genes to re­store a healthy im­mune sys­tem.

In try­ing to tap an­i­mal mi­cro­bio­mes and iso­late in­di­vid­ual pro­teins, Raab and Bachelet will have to show a deep­er un­der­stand­ing of the bac­te­ria and the func­tion of the genes they un­cov­ered. They say they have that tech­nol­o­gy and they’ve re­ceived an em­i­nent backer in Is­raeli bil­lion­aire Mar­ius Nacht, but so far, it re­mains un­pub­lished and un­proven.

“My guess is that there’s gonna be a lot of valu­able med­i­c­i­nal in­for­ma­tion in there,” says Dan Littman, a pro­fes­sor of mol­e­c­u­lar im­munol­o­gy at NYU and co-founder of the mi­cro­bio­me biotech Vedan­ta. “But it’s go­ing to take an enor­mous amount of work to go from here to the next step of mak­ing a valu­able prod­uct.”

A hye­na cre­at­ing a mi­cro­bio­me sam­ple in Ugan­da. Re­searchers will col­lect it with­in the hour (Gal Zanir)

Click on the im­age to see the full-sized ver­sion

A se­cre­tive Is­raeli in­sti­tute with some bird ques­tions

Wild Biotech grew out of work Raab, Bachelet and their third co­founder, Doron Levin, con­duct­ed at a small in­sti­tute in Re­hovot, Is­rael called Aug­man­i­ty. Bachelet did his post­doc at the Church lab, where he start­ed mak­ing a name in a field of nan­otech­nol­o­gy called DNA origa­mi, and he says he found­ed Aug­man­i­ty af­ter leav­ing acad­e­mia to back am­bi­tious sci­en­tif­ic projects. But he of­fered no oth­er de­tails, in­clud­ing what oth­er work they do or how many peo­ple work there.

“We’re a very stealthy or­ga­ni­za­tion,” Bachelet says, point­ing me to a sin­gle-page web­site that was of­fline at the time. “There’s no sign on the build­ing, there’s no sign on the door.”

Raab, a for­mer stu­dent and now Wild’s CEO, joined Aug­man­i­ty af­ter her own stint at the Church lab, hop­ing to help build Is­rael’s biotech scene.

The mi­cro­bio­me project arose out of sev­er­al ideas they had about birds: Is­rael is a land­ing spot for bil­lions of birds mi­grat­ing be­tween Africa and Eu­rope — could they sam­ple their drop­pings and warn coun­tries of the path­o­gen­ic bac­te­ria they car­ry? They al­so won­dered about the mi­cro­bio­mes in vul­tures and oth­er scav­engers. These an­i­mals eat rot­ting flesh, so they need to evade or with­stand the tox­ins in the bac­te­ria that grow on corpses. Did they use their own mi­cro­bio­mes to do so?

Soon, they were ask­ing about all sorts of dif­fer­ent an­i­mals and how they sur­vived con­di­tions hu­mans nev­er en­counter. “So the idea was born from many dif­fer­ent small ques­tions,” Raab says. “But at some point, we kind of had an epiphany.”

Raab worked with ex­perts from the Is­raeli sa­fari and IDF spe­cial­ists to track an­i­mals in Hun­gary, Ugan­da, the Falk­land Is­lands, Mada­gas­car, Aus­tralia and Is­rael. They used drones to fol­low an­i­mals and teamed with guides and rangers to track them by foot and ve­hi­cle. They put up nets to trap and band birds. They board­ed in­flat­able boats to trail whales off the Falk­land Is­lands, skim­ming sam­ples on the wa­ter’s sur­face.

Along with the fe­cal sam­ple, track­ers al­so logged de­tails about the in­di­vid­ual an­i­mal and lo­ca­tion. Oth­er re­searchers have looked at a wide range of cap­tive an­i­mals, but Raab want­ed wild an­i­mals, point­ing to re­search that cap­tiv­i­ty can change or even crip­ple an an­i­mal’s mi­cro­bio­me.

“It changes their ca­pac­i­ty to re­turn to na­ture,” she says. “And we re­al­ly want­ed to look for the spe­cif­ic fea­tures that en­able them to re­al­ly sur­vive in the hos­tile and harsh en­vi­ron­ments.”

To an­a­lyze the sam­ples af­ter they ar­rived in Is­rael, Bachelet and Raab reached out to Se­gal, a pi­o­neer in com­pu­ta­tion­al ge­net­ics who some­times worked on the hu­man mi­cro­bio­me. The two labs broke the DNA they ex­tract­ed — a tan­gle of strands from all the var­i­ous mi­crobes in a giv­en fe­cal sam­ple called a “metagenome” —  in­to small pieces that can be read by a se­quencer. The se­quencer spits out an in­com­pre­hen­si­ble jum­ble of frag­ments from hun­dreds or thou­sands of dif­fer­ent bac­te­ria. But by look­ing for places where the dif­fer­ent frag­ments over­lap, the re­searchers can stitch com­plete genomes back to­geth­er.

They can then tag in­di­vid­ual genes by look­ing for rec­og­niz­able pat­terns. Every gene, for ex­am­ple, starts and ends with string of let­ters called a “start” and “stop” codon.

“A metagenome is like an in­com­plete jig­saw puz­zle thrown on the floor,” says Gilbert, the UCSD re­searcher. “What they’ve done is take those puz­zle pieces and start to piece them to­geth­er.”

Sur­pris­ing in­sights

The work im­me­di­ate­ly brought sur­pris­es. David Zee­vi, a PhD stu­dent at Se­gal’s lab who worked on the metagenome analy­sis, says bac­te­ria that live on land and in the sea gen­er­al­ly have sim­i­lar genomes. So he was shocked by how much the mi­cro­bio­mes could vary be­tween species and how many new genes ap­peared.

“They have such a huge di­ver­si­ty, huge po­ten­tial of new mi­cro­bial genes,” says Zee­vi, who is now an in­de­pen­dent fel­low at Rock­e­feller about to launch his own mi­cro­bio­me lab at the Weiz­mann In­sti­tute. “What are the se­lec­tive pres­sures, in terms of evo­lu­tion, that led to some­thing like this?”

For Bachelet and Raab, though, the big ques­tion is whether they can trans­late the data­base in­to drugs. They be­gan link­ing the genes they found to traits in the pa­per, show­ing for ex­am­ple dif­fer­ences be­tween car­ni­vores and her­bi­vores that might give meat-eaters en­hanced abil­i­ties to com­bat tox­ic bac­te­ria.

As a proof-of-con­cept, they syn­the­sized one pro­tein found in grif­fon vul­tures’ mi­cro­bio­me they be­lieved helped it com­bat the dead­ly synapse-cut­ting poi­son bot­u­linum tox­in A. It turned out that the pro­tein ac­tu­al­ly sped up the tox­in’s ef­fect — part of what the re­searchers be­lieve is a cas­cade of en­zymes grif­fons use to clear it.

Bot­u­linum tox­in A is al­so the key in­gre­di­ent in Ab­b­Vie bil­lion-dol­lar Botox. Per­haps, Bachelet says, you can use the grif­fon pro­tein to cre­ate a fast-act­ing Botox, or “Su­per-Botox.” “That’s al­ready a mar­ket,” he says.

Naa­ma Ge­va Za­torsky

Naa­ma Ge­va-Za­torsky, who runs a sys­tems bi­ol­o­gy lab at the Tech­nion, agreed the tox­in pro­vid­ed a good test case, adding that she’d now like to see larg­er work on col­lect­ing, study­ing and freez­ing an­i­mal mi­cro­bio­me sam­ples, as re­searchers have done with hu­man mi­cro­bio­mes.

“This is a pure­ly beau­ti­ful study!” she said in an email. “Trans­lat­ing to med­i­cine is to­tal­ly fea­si­ble.”

Not every­one is con­vinced, though. David Berry, a part­ner at Flag­ship who played a piv­otal role in found­ing the mi­cro­bio­me biotechs Seres Ther­a­peu­tics, Evelo Bio­sciences and In­di­go Agri­cul­ture, says their work brought ma­jor in­sights in­to an un­der-ex­plored area. In the past, though, he says re­searchers have strug­gled to iso­late in­di­vid­ual genes that give a par­tic­u­lar gut bac­teri­um its im­pact.

David Berry

Of­ten­times, sci­en­tists would see two strains of the same species, one that has a pro­found ef­fect on its host and one that doesn’t. But when they tried to com­pare the two genomes to find the dif­fer­ence, they would find mil­lions of dif­fer­ences — on the same scale that sep­a­rates hu­man and ba­nanas, say, or hu­mans and fun­gi — mak­ing it im­pos­si­ble to sin­gle out a pro­tein that could be ther­a­peu­tic.

Still, he adds, some­times they found chem­i­cals pro­duced by the mi­crobes that were piv­otal.

“I wouldn’t rule out the po­ten­tial that there’s some­thing deeply im­por­tant and deeply in­sight­ful in the da­ta,” he says. “But I think there’s a whole bunch of steps that have to be tak­en to turn this in­to some­thing that can pro­duce drugs.”

A wild fu­ture 

Bachelet and Raab are now work­ing on those steps. So far they’re keep­ing most de­tails about the com­pa­ny un­der wraps. They say they have a far larg­er data­base than the one they pub­lished in Sci­ence and an AI-as­sist­ed soft­ware that can link the in­di­vid­ual genes they found to po­ten­tial im­pact par­tic­u­lar dis­or­ders.

They’re fo­cus­ing, Bachelet says, on pro­teins and func­tions you can’t find in the hu­man mi­cro­bio­me and that might of­fer new routes of ad­min­is­tra­tion or the abil­i­ty to rad­i­cal­ly al­ter the im­mune sys­tem. With bil­lion­aire Nacht’s back­ing, they’ve built a 9-per­son-team with­out hav­ing to re­ly on tra­di­tion­al VC fund­ing.

The com­pa­ny has a cou­ple lead can­di­dates from the ini­tial analy­sis and they’ll work on ex­pand­ing the plat­form and re­fin­ing the soft­ware for at least the next year, be­fore they po­ten­tial­ly need more fund­ing. In the mean­time, they’ve frozen all their old sam­ples should they need to be test­ed again or if they want to try to cul­ture in­di­vid­ual strains liv­ing in­side. It’s a one-of-a-kind re­source for the fu­ture.

“We’re heads down,” Raab says. “It’s ear­ly, still.”

ZS Per­spec­tive: 3 Pre­dic­tions on the Fu­ture of Cell & Gene Ther­a­pies

The field of cell and gene therapies (C&GTs) has seen a renaissance, with first generation commercial therapies such as Kymriah, Yescarta, and Luxturna laying the groundwork for an incoming wave of potentially transformative C&GTs that aim to address diverse disease areas. With this renaissance comes several potential opportunities, of which we discuss three predictions below.

Allogenic Natural Killer (NK) Cells have the potential to displace current Cell Therapies in oncology if proven durable.

Despite being early in development, Allogenic NKs are proving to be an attractive new treatment paradigm in oncology. The question of durability of response with allogenic therapies is still an unknown. Fate Therapeutics’ recent phase 1 data for FT516 showed relatively quicker relapses vs already approved autologous CAR-Ts. However, other manufacturers, like Allogene for their allogenic CAR-T therapy ALLO-501A, are exploring novel lymphodepletion approaches to improve persistence of allogenic cells. Nevertheless, allogenic NKs demonstrate a strong value proposition relative to their T cell counterparts due to comparable response rates (so far) combined with the added advantage of a significantly safer AE profile. Specifically, little to no risk of graft versus host disease (GvHD), cytotoxic release syndrome (CRS), and neurotoxicity (NT) have been seen so far with allogenic NK cells (Fig. 1). In addition, being able to harness an allogenic cell source gives way to operational advantages as “off-the-shelf” products provide improved turnaround time (TAT), scalability, and potentially reduced cost. NKs are currently in development for a variety of overlapping hematological indications with chimeric antigen receptor T cells (CAR-Ts) today, and the question remains to what extent they will disrupt the current cell therapy landscape. Click for more details.

Graphic: Kathy Wong for Endpoints News

What kind of biotech start­up wins a $3B syn­di­cate, woos a gallery of mar­quee sci­en­tists and re­cruits GSK's Hal Bar­ron as CEO in a stun­ner? Let Rick Klaus­ner ex­plain

It started with a question about a lifetime’s dream on a walk with tech investor Yuri Milner.

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Milner’s question on one of those mornings on foot: “What do you want to do?”

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Hal Barron, Endpoints UKBIO20 (Jeff Rumans)

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Executive Director of the EMA Emer Cooke (AP Photo/Geert Vanden Wijngaert)

Eu­ro­pean Par­lia­ment signs off on strength­en­ing drug reg­u­la­tor's abil­i­ty to tack­le short­ages

The European Parliament on Thursday endorsed a plan to increase the powers of the European Medicines Agency, which will be better equipped to monitor and mitigate shortages of drugs and medical devices.

By a vote of 655 to 31, parliament signed off on a provisional agreement reached with the European Council from last October, in which the EMA will create two shortage steering groups (one for drugs, the other for devices), a new European Shortages Monitoring Platform to facilitate data collection and increase transparency, and on funding for the work of the steering groups, task force, working parties and expert panels that are to be established.

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Sec­ondary patents prove to be key in biosim­i­lar block­ing strate­gies, re­searchers find

While the US biosimilars industry has generally been a disappointment since its inception, with FDA approving 33 biosimilars since 2015, just a fraction of those have immediately followed their approvals with launches. And more than a handful of biosimilars for two of the biggest blockbusters of all time — AbbVie’s Humira and Amgen’s Enbrel — remain approved by FDA but still have not launched because of legal settlements.

Hal Barron (GSK via YouTube)

GSK R&D chief Hal Bar­ron jumps ship to run a $3B biotech start­up, Tony Wood tapped to re­place him

In a stunning switch, GlaxoSmithKline put out word early Wednesday that R&D chief Hal Barron is exiting the company after 4 years — a relatively brief run for the man chosen by CEO Emma Walmsley in late 2017 to turn around the slow-footed pharma giant.

Barron is being replaced by Tony Wood, a close associate of Barron’s who’s taking one of the top jobs in Big Pharma R&D. He’ll be closer to home, though, for GSK. Barron has been running a UK and Philadelphia-based research organization from his perch in San Francisco.

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Troy Wilson, Kura CEO

FDA lifts par­tial hold on Ku­ra's Phase Ib AML pro­gram as biotech re­dou­bles mit­i­ga­tion ef­forts

Kura Oncology is clear to resume studies for its early-stage leukemia program after the FDA lifted a clinical hold Thursday afternoon.

Regulators had placed the hold on a Phase Ib study of KO-539, an experimental oral treatment for some genetic subsets of acute myeloid leukemia last November after a patient died while taking the drug. Kura expects to begin enrolling patients again imminently, CEO Troy Wilson told Endpoints News.

A Sen­ate bill wants to even an 'un­lev­el play­ing field' for do­mes­tic, for­eign in­spec­tion drop-ins amid back­log

Amid geopolitical tensions between the US and China, two Republican senators are calling for a bill that would aim to strike a balance on domestic and foreign inspection requirements from the FDA.

Sens. Mike Braun (R-IN) and Joni Ernst (R-IA) have penned a bill called the Creating Efficiency in Foreign Inspections Act. It contains a bit of rhetoric, highlighting “communist China” not once, but twice in the release, but states that the goal is to even the playing field between foreign and American manufacturers.

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